Steric effects sodium borohydride reduction

In order to determine whether or not added steric effects in using a-methylbenzyl contributed to the induction of R configuration in the sodium borohydride reduction, the same sequence of reactions was carried out employing RS-a-methylbenzylamine. Analysis of the products from both reaction sequences gave the results summarized in Table 2. 

Much emphasis has been placed on the selectivity of quaternary ammonium borohydrides in their reduction of aldehydes and ketones [18-20]. Predictably, steric factors are important, as are mesomeric electronic effects in the case of 4-substituted benzaldehydes. However, comparison of the relative merits of the use of tetraethyl-ammonium, or tetra-n-butylammonium borohydride in dichloromethane, and of sodium borohydride in isopropanol, has shown that, in the competitive reduction of benzaldehyde and acetophenone, each system preferentially reduces the aldehyde and that the ratio of benzyl alcohol to 1-phenylethanol is invariably ca. 4 1 [18-20], Thus, the only advantage in the use of the ammonium salts would appear to facilitate the use of non-hydroxylic solvents. In all reductions, the use of the more lipophilic tetra-n-butylammonium salt is to be preferred and the only advantage in using the tetraethylammonium salt is its ready removal from the reaction mixture by dissolution in water. 

In fact, there is a great variety of methods for achieving the synthesis of less stable configurations, which depend upon steric and proximity effects. Such processes, as for instance the reduction of an 11-ketosteroid with sodium borohydride to give the axially disposed 11-p-OH, are explained by the attack of the reagent from the less hindered a-face of the molecule. 

Reduction of 5,6/3-dibromo-5a-cholestan-3-one (128) by sodium borohydride in ethanol is subject to steric effects, giving cholest-5-en-3a-ol (130) as the main product. The 3a-hydroxy-5a,6/3-dibromide (129) is thought to be formed first and to suffer reductive elimination of the bromo-substituents with participation by the 3a-hydroxy-group.135 This convenient route to the 5-en-3a-oI is competitive in yields with some older routes. 

Cyclopentyl radicals substituted in the /1-position relative to the radical center are formed during the solvomercuration/reductive alkylation reaction of cyclopentene34. The organomer-curial produced in the first solvomercuration step is reduced by sodium borohydride and yields free cyclopentyl radicals in a radical chain mechanism. Addition of alkenes can then occur tram or cis to the / -alkoxy substituent introduced during the solvomercuration step. The adduct radical is finally trapped by hydrogen transfer from mercury hydrides to yield the tram- and ris-addition products, The transicis ratio depends markedly on the alkene employed and it appears that the addition of less reactive alkenes occurs with higher trans selectivity. In reactions of highly substituted alkenes, this reactivity control is compensated for by steric effects. Therefore, only the fnms-addition product is observed in reactions of tetraethyl ethenetetracarboxylate. The choice of alcohol employed in the solvomercuration step has, however, only a small influence on the stereoselectivity. 

Reduction of 4-methyl-3-methylthio-l,2,4-triazin-5(4//)-ones (232) with sodium borohydride usually afforded the 1,6-dihydro products (233) selectively (Equation (25)), but the 6-t-butyl compound (234) gave mainly the 2,3-dihydro compound (235) (Equation (26)). The influence of the steric and electronic effects of the substituents at the 3- and 6-positions upon the product ratio was studied <84JHC639>. 

The data show that reduction of carbonyls with 9-BBN is less susceptible to steric effects than is sodium borohydride, in spite of the bulky nature of the former reagent. For example, cyclooctanone is reduced by 9-BBN by a factor of 50 slower than cyclohexanone. Whereas the factor is as much as 2,050 for reduction with sodium borohydride [3c]. 

When the ketones are relatively hindered—as, for example, in the bicyclo[2.2.1]heptan-2-one system—steric effects govern the stereochemistry of reduction even for small hydride reagents such as sodium borohydride and lithium aluminum hydride. 

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